Celecoxib, also known as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (I), the active ingredient of Celebrex® marketed by Pharmacia Corp., has a therapeutically and prophylactically useful selective cyclooxygenase-2 inhibitory effect, and has utility in treatment and prevention of specific cyclooxygenase-2 mediated disorders and of such disorders in general. Celecoxib has the structure:

Processes for preparing celecoxib are set forth in U.S. Pat. No. 5,466,823 to Talley et al. and in U.S. Pat. No. 5,892,053 to Zhi & Newaz, both incorporated herein by reference. Co-assigned International Patent Publication No. WO 00/32189, incorporated herein by reference, discloses that celecoxib has a crystal morphology which tends to form long, cohesive needles. Co-assigned International Patent Publication No. WO 00/42021, incorporated herein by reference, discloses a solvated crystalline form of celecoxib and a method for desolvation of that crystalline form.
A need for new forms of celecoxib, in particular forms suitable for preparing rapid-onset compositions, exists. Rapid-onset drug-delivery systems can provide significant benefits over conventional dosage forms. Generally, rapid-onset preparations provide a short period to therapeutic or prophylactic response compared to conventional immediate-release or sustained-release dosage forms. For example, in treatment of acute pain, a rapid-onset dosage form of celecoxib would be useful to provide fast pain relief.
However, celecoxib presents certain challenges for formulation as a rapid-onset dosage form, particularly as a rapid-onset oral dosage form. For example, celecoxib has very low solubility in aqueous media and therefore is not readily dissolved and dispersed for rapid absorption in the gastrointestinal tract when administered orally, for example in tablet or capsule form. In addition, celecoxib has a relatively high dose requirement further increasing difficulties of providing a sufficient therapeutically effective dose for rapid absorption.
Celecoxib crystals also present formulation difficulties as a result of unique physical and chemical characteristics or mechanical properties such as electrostatic and cohesive properties, low bulk density, low compressibility and poor flow properties. Due at least in part to these properties, celecoxib crystals tend to segregate and agglomerate together during mixing, resulting in a non-uniformly blended composition containing undesirably large, insoluble aggregates of celecoxib. For these and other reasons, therefore, it is difficult to prepare an orally deliverable, rapid-onset composition containing celecoxib that has the desired blend uniformity.
The bioavailability of an orally administered drug, as measured by its entry into systemic circulation in the bloodstream, depends on at least two fundamental processes: drug dissolution in gastrointestinal fluids (in vivo drug release) and subsequent absorption of the dissolved drug. Several factors influence dissolution of a drug from its carrier, including surface area of the drug presented to the dissolution solvent medium, solubility of the drug substance in the solvent medium, and driving forces of the saturation concentration of dissolved materials in the solvent medium.
When the process of in vivo drug release is slower than the process of absorption, absorption is said to be dissolution rate-limited. Since dissolution precedes absorption in the overall process, any change in the drug release or dissolution process will subsequently influence drug absorption. See for example Lieberman et al. (1989), Pharmaceutical Dosage Forms: Tablets, Vol. 1, pp. 34–36. Marcel Dekker, New York. It is clear, therefore, that dissolution time determined for a composition is one of the important fundamental characteristics for consideration when evaluating compositions intended for fast-onset delivery, particularly where drug absorption is dissolution rate-limited.
Crystalline solids, due to their highly organized, lattice-like structures, typically require a significant amount of energy for dissolution. The energy required for a drug molecule to escape from a crystal, for example, is greater than is required for the same drug molecule to escape from a non-crystalline, amorphous form. Importantly, however, crystalline drug forms which have been transformed into amorphous forms tend to revert to a steady state of low energy, namely the crystalline form, over time and thus may not have an adequate shelf life. An amorphous form of celecoxib has not hitherto been known in the art.
As indicated hereinbelow, treatment with celecoxib is indicated in a very wide array of cyclooxygenase-2 mediated conditions and disorders. Therefore, if an amorphous form of celecoxib could be prepared, and in particular if a storage-stable composition comprising such an amorphous form of celecoxib could be developed exhibiting enhanced bioavailability, for example through rapid dissolution of the drug, a significant advance would be realized in treatment of cyclooxygenase-2 mediated conditions and disorders, particularly in treatment of acute disorders where early relief from pain or other symptoms is desired.